Laser-Induced Synthesis of Tin Sulfides.

Various polytypes of van der Waals (vdW) materials can be formed by sulfur and tin, which exhibit distinctive and complementary electronic properties. Hence, these materials are attractive candidates for the design of multifunctional devices. This work demonstrates direct selective growth of tin sulfides by laser irradiation. A 532 nm continuous wave laser is used to synthesize centimeter-scale tin sulfide tracks from single source precursor tin(II) o-ethylxanthate under ambient conditions. Modulation of laser irradiation conditions enables tuning of the dominant phase of tin sulfide as well as SnS2/SnS heterostructures formation. An in-depth investigation of the morphological, structural, and compositional characteristics of the laser-synthesized tin sulfide microstructures is reported. Furthermore, laser-synthesized tin sulfides photodetectors show broad spectral response with relatively high photoresponsivity up to 4 AW-1 and fast switching time (τ rise = 1.8 ms and τ fall = 16 ms). This approach is versatile and can be exploited in various fields such as energy conversion and storage, catalysis, chemical sensors, and optoelectronics.

Nanosized Chevrel phases for dendrite-free zinc-ion based energy storage: unraveling the phase transformations.

The nanoscale form of the Chevrel phase, Mo6S8, is demonstrated to be a highly efficient zinc-free anode in aqueous zinc ion hybrid supercapacitors (ZIHSCs). The unique morphological characteristics of the material when its dimensions approach the nanoscale result in fast zinc intercalation kinetics that surpass the ion transport rate reported for some of the most promising materials, such as TiS2 and TiSe2. In situ Raman spectroscopy, post-mortem X-ray diffraction, Hard X-ray photoelectron spectroscopy, and density functional theory (DFT) calculations were combined to understand the overall mechanism of the zinc ion (de)intercalation process. The previously unknown formation of the sulfur-deficient Zn2.9Mo15S19 (Zn1.6Mo6S7.6) phase is identified, leading to a re-evaluation of the mechanism of the (de)intercalation process. A full cell comprised of an activated carbon (YEC-8A) positive electrode delivers a cell capacity of 38 mA h g-1 and an energy density of 43.8 W h kg-1 at a specific current density of 0.2 A g-1. The excellent cycling stability of the device is demonstrated for up to 8000 cycles at 3 A g-1 with a coulombic efficiency close to 100%. Post-mortem microscopic studies reveal the absence of dendrite formation at the nanosized Mo6S8 anode, in stark contrast to the state-of-the-art zinc electrode.

Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study.

BACKGROUND: A standard of care and optimal duration of therapy have not been established for patients with multiply relapsed or refractory follicular lymphoma. The aim of this study was to evaluate epcoritamab, a novel CD3 × CD20 bispecific antibody, in the third-line and later setting of follicular lymphoma. METHODS: EPCORE NHL-1 is a multicohort, single-arm, phase 1-2 trial conducted at 88 sites across 15 countries. Here, we report the primary analysis of patients with relapsed or refractory follicular lymphoma in the phase 2 part of the trial, which included the pivotal (dose expansion) cohort and the cycle 1 optimisation cohort. Eligible patients were aged 18 years or older, had relapsed or refractory CD20+ follicular lymphoma (grade 1-3A), an Eastern Cooperative Oncology Group performance status of up to 2, and had received at least two previous lines of therapy (including an anti-CD20 monoclonal antibody and an alkylating agent or lenalidomide). Patients were treated with subcutaneous epcoritamab 48 mg in 28-day cycles: weekly in cycles 1-3, biweekly in cycles 4-9, and every 4 weeks until disease progression or unacceptable toxicity. To mitigate the risk and severity of cytokine release syndrome, in the pivotal cohort, cycle 1 consisted of a step-up dosing regimen of a 0·16-mg priming dose on day 1 and a 0·80-mg intermediate dose on day 8, followed by subsequent 48-mg full doses and prophylactic prednisolone 100 mg; in the cycle 1 optimisation cohort, a second intermediate dose of 3 mg on day 15, adequate hydration, and prophylactic dexamethasone 15 mg were evaluated during cycle 1 to further reduce risk and severity of cytokine release syndrome. Primary endpoints were independently reviewed overall response rate for the pivotal cohort and the proportion of patients with grade 2 or worse and any-grade cytokine release syndrome for the cycle 1 optimisation cohort. Analyses were done in all enrolled patients who had received at least one dose of epcoritamab. This study is registered with ClinicalTrials.gov, NCT03625037, and is ongoing. FINDINGS: Between June 19, 2020, and April 21, 2023, 128 patients (median age 65 years [IQR 55-72]; 49 [38%] female and 79 [62%] male) were enrolled and treated in the pivotal cohort (median follow-up 17·4 months [IQR 9·1-20·9]). The overall response rate was 82·0% (105 of 128 patients; 95% CI 74·3-88·3), with a complete response rate of 62·5% (80 of 128; 95% CI 53·5-70·9). The most common grade 3-4 treatment-emergent adverse event was neutropenia in 32 (25%) of 128 patients. Grade 1-2 cytokine release syndrome was reported in 83 (65%) of 128 patients; grade 3 cytokine release syndrome was reported in two (2%). Immune effector cell-associated neurotoxicity syndrome was reported in eight (6%) of 128 patients (five [4%] grade 1; three [2%] grade 2). Between Oct 25, 2022, and Jan 8, 2024, 86 patients (median age 64 years [55-71]; 37 [43%] female and 49 [57%] male) were enrolled and treated in the cycle 1 optimisation cohort. The incidence of cytokine release syndrome was 49% (42 of 86 patients; eight [9%] grade 2; none of grade 3 or worse), with no reported immune effector cell-associated neurotoxicity syndrome. INTERPRETATION: Epcoritamab monotherapy showed clinically meaningful activity in patients with multiply relapsed or refractory follicular lymphoma, and had a manageable safety profile. FUNDING: Genmab and AbbVie.

Aging disrupts the coordination between mRNA and protein expression in mouse and human midbrain.

Age-related dopamine (DA) neuron loss is a primary feature of Parkinson's disease. However, it remains unclear whether similar biological processes occur during healthy aging, albeit to a lesser degree. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans. In mice, we identified no changes in midbrain neuron numbers throughout aging. Despite this, we found age-related decreases in midbrain mRNA expression of tyrosine hydroxylase (Th), the rate limiting enzyme of DA synthesis. Among midbrain glutamatergic cells, we similarly identified age-related declines in vesicular glutamate transporter 2 (Vglut2) mRNA expression. In co-transmitting Th +/Vglut2 + neurons, Th and Vglut2 transcripts decreased with aging. Importantly, striatal Th and Vglut2 protein expression remained unchanged. In translating our findings to humans, we found no midbrain neurodegeneration during aging and identified age-related decreases in TH and VGLUT2 mRNA expression similar to mouse. Unlike mice, we discovered diminished density of striatal TH+ dopaminergic terminals in aged human subjects. However, TH and VGLUT2 protein expression were unchanged in the remaining striatal boutons. Finally, in contrast to Th and Vglut2 mRNA, expression of most ribosomal genes in Th + neurons was either maintained or even upregulated during aging. This suggests a homeostatic mechanism where age-related declines in transcriptional efficiency are overcome by ongoing ribosomal translation. Overall, we demonstrate species-conserved transcriptional effects of aging in midbrain dopaminergic and glutamatergic neurons that are not accompanied by marked cell death or lower striatal protein expression. This opens the door to novel therapeutic approaches to maintain neurotransmission and bolster neuronal resilience.

Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition.

Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.

Synaptic alterations in pyramidal cells following genetic manipulation of neuronal excitability in monkey prefrontal cortex.

In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) are thought to receive fewer excitatory synaptic inputs and to have lower expression levels of activity-dependent genes and of genes involved in mitochondrial energy production. In concert, these findings from previous studies suggest that DLPFC L3PNs are hypoactive in schizophrenia, disrupting the patterns of activity that are crucial for working memory, which is impaired in the illness. However, whether lower PN activity produces alterations in inhibitory and/or excitatory synaptic strength has not been tested in the primate DLPFC. Here, we decreased PN excitability in rhesus monkey DLPFC in vivo using adeno-associated viral vectors (AAVs) to produce Cre recombinase-mediated overexpression of Kir2.1 channels, a genetic silencing tool that efficiently decreases neuronal excitability. In acute slices prepared from DLPFC 7-12 weeks post-AAV microinjections, Kir2.1-overexpressing PNs had a significantly reduced excitability largely attributable to highly specific effects of the AAV-encoded Kir2.1 channels. Moreover, recordings of synaptic currents showed that Kir2.1-overexpressing DLPFC PNs had reduced strength of excitatory synapses whereas inhibitory synaptic inputs were not affected. The decrease in excitatory synaptic strength was not associated with changes in dendritic spine number, suggesting that excitatory synapse quantity was unaltered in Kir2.1-overexpressing DLPFC PNs. These findings suggest that, in schizophrenia, the excitatory synapses on hypoactive L3PNs are weaker and thus might represent a substrate for novel therapeutic interventions. Significance Statement: In schizophrenia, dorsolateral prefrontal cortex (DLPFC) pyramidal neurons (PNs) have both transcriptional and structural alterations that suggest they are hypoactive. PN hypoactivity is thought to produce synaptic alterations in schizophrenia, however the effects of lower neuronal activity on synaptic function in primate DLPFC have not been examined. Here, we used, for the first time in primate neocortex, adeno-associated viral vectors (AAVs) to reduce PN excitability with Kir2.1 channel overexpression and tested if this manipulation altered the strength of synaptic inputs onto the Kir2.1-overexpressing PNs. Recordings in DLPFC slices showed that Kir2.1 overexpression depressed excitatory (but not inhibitory), synaptic currents, suggesting that, in schizophrenia, the hypoactivity of PNs might be exacerbated by reduced strength of the excitatory synapses they receive.

Thermoelectric Performance of Tetrahedrite (Cu12Sb4S13) Thin Films: The Influence of the Substrate and Interlayer.

In the present work, tetrahedrite Cu12Sb4S13 thin films were deposited on various substrates via aerosol-assisted chemical vapor deposition (AACVD) using diethyldithiocarbamate complexes as precursors. A buffer layer of Sb2O3 with a small lattice mismatch to Cu12Sb4S13 was applied to one of the glass substrates to improve the quality of the deposited thin film. The buffer layer increased the coverage of the Cu12Sb4S13 thin film, resulting in improved electrical transport properties. The growth of the Cu12Sb4S13 thin films on the other substrates, including ITO-coated glass, a SiO2-coated Si wafer, and mica, was also investigated. Compared to the films grown on the other substrates, the Cu12Sb4S13 thin film deposited on the SiO2-coated Si wafer showed a dense and compact microstructure and a larger grain size (qualities that are beneficial for carrier transport), yielding a champion power factor (PF) of ∼362 µW cm-1 K-2 at 625 K. The choice of substrate strongly influenced the composition, microstructure, and electrical transport properties of the deposited Cu12Sb4S13 thin film. At 460 K, the highest zT value that was obtained for the thin films was ∼0.18. This is comparable to values reported for Cu-Sb-S bulk materials at the same temperature. Cu12Sb4S13 thin films deposited using AACVD are promising for thermoelectric applications. To the best of our knowledge, the first full thermoelectric characterization of the Cu12Sb4S13 thin film is performed in this work.

Developmental stage and level of submersion in water impact the viability of lone star and winter tick eggs during flooding.

Female ticks deposit large egg clusters that range in size from hundreds to thousands. These clusters are restricted to a deposition site, usually under leaf litter and other debris. These sites can be exposed to periodic flooding, where the cluster of tick eggs can float to the surface or remain underneath organic debris entirely underwater. Here, we examined the viability of egg clusters from winter ticks, Dermacentor albipictus , and lone star ticks, Amblyomma americanum , when partially submerged or fully submerged in water in relation to the developmental stages of the eggs. In general, egg clusters that were older and partially submerged had a higher viability than fully submerged, young eggs in water. A. americanum was much more resistant to water exposure between the two species. These studies highlight that egg clusters for specific tick species can remain viable when exposed to water for at least two weeks, where eggs float on the surface. These studies also suggest that water-based distribution of egg clusters could occur for some species, and flooding will differentially impact tick egg survival based on the specific developmental stage of exposure and species.

Oxidative stress contributes to hypermethylation of Histone H3 lysine 9 in placental trophoblasts from preeclamptic pregnancies.

Background and objective: Aberrant epigenetic regulation and increased oxidative stress in the placenta play a significant role in placental pathophysiology and fetal programming in preeclampsia, a hypertensive disorder in human pregnancy. The purpose of the study is to investigate if hypermethylation of histone H3K9 occurs in placental trophoblasts from preeclampsia. Methods: Trophoblasts were isolated and cultured from 14 placentas, 7 from normotensive pregnant women and 7 from preeclamptic pregnancies. Methylated H3K9 expression and antioxidant superoxide dismutase expression were determined by Western blot. We also examined consequences of oxidative stress and the downstream effects of histone methyltransferase inhibition on H3K9 expression associated with antioxidant CuZn-SOD and Mn-SOD expression in placental trophoblasts. Results: We found that expression of mono-, di-, and tri-methylation of histone H3 lysine 9 (H3K9me1, H3K9me2 and H3K9me3) was significantly increased, p<0.01, which correlated with downregulation of antioxidant superoxide dismutase CuZn-SOD and Mn-SOD expression, in trophoblasts from preeclamptic placentas compared to those from uncomplicated control placentas. We further demonstrated hypoxia could promote histone H3K9 methylation in placental trophoblasts, and hypoxia-induced upregulation of H3K9me1, H3K9me2 and H3K9me3 expression was reversible when hypoxic condition was removed. In addition, we also uncovered that inhibition of methyltransferase not only prevented hypoxia-induced upregulation of H3K9me1, H3K9me2 and H3K9me3 expression, but also abolished hypoxia-induced downregulation of CuZn-SOD and Mn-SOD expression in placental trophoblasts. Conclusions: These findings are noteworthy and provide further evidence that increased oxidative stress in the intrauterine environment is likely a mechanism to induce aberrant histone modification in placental trophoblasts in preeclampsia. Moreover, CuZn-SOD and Mn-SOD expression/activity are possibly H3K9 methylation-dependent in placental trophoblasts, which further suggest that oxidative stress and aberrant histone modification have significant impact on placental trophoblasts/fetal programming in preeclampsia.

Genetic regulation of cell type-specific chromatin accessibility shapes brain disease etiology.

Nucleotide variants in cell type-specific gene regulatory elements in the human brain are risk factors for human disease. We measured chromatin accessibility in 1932 aliquots of sorted neurons and non-neurons from 616 human postmortem brains and identified 34,539 open chromatin regions with chromatin accessibility quantitative trait loci (caQTLs). Only 10.4% of caQTLs are shared between neurons and non-neurons, which supports cell type-specific genetic regulation of the brain regulome. Incorporating allele-specific chromatin accessibility improves statistical fine-mapping and refines molecular mechanisms that underlie disease risk. Using massively parallel reporter assays in induced excitatory neurons, we screened 19,893 brain QTLs and identified the functional impact of 476 regulatory variants. Combined, this comprehensive resource captures variation in the human brain regulome and provides insights into disease etiology.

Omics approaches to investigate the pathogenesis of suicide.

Suicide is the second leading cause of death in U.S. adolescents and young adults, and generally associated with a psychiatric disorder. Suicidal behavior has a complex etiology and pathogenesis. Moderate heritability suggests genetic causes. Associations between childhood and recent life adversity indicate contributions from epigenetic factors. Genomic contributions to suicide pathogenesis remain largely unknown. This paper is based on a workshop held to design strategies to identify molecular drivers of suicide neurobiology that would be putative new treatment targets. The panel determined that, while bulk tissue studies provide comprehensive information, single-nucleus approaches identifying cell-type specific changes are needed. While single nuclei techniques lack information on cytoplasm, processes, spines, and synapses, spatial multiomic technologies on intact tissue detect cell alterations specific to brain tissue layers and subregions. Because suicide has genetic and environmental drivers, multiomic approaches combining cell-type specific epigenome, transcriptome, and proteome provide a more complete picture of pathogenesis. To determine the direction of effect of suicide risk gene variants on RNA and protein expression, and how these interact with epigenetic marks, single nuclei and spatial multiomics quantitative trait loci maps should be integrated with whole genome sequencing and genome-wide association databases. The workshop concluded with the recommendation for the formation of an international suicide biology consortium that will bring together brain banks and investigators with expertise in cutting-edge omics technologies to delineate the biology of suicide and identify novel potential treatment targets to be tested in cellular and animal models for drug and biomarkers discovery, to guide suicide prevention.

Semiconductor Deposition via Laser Printing of a Bespoke Toner Containing Metal Xanthate Complexes.

A methodology to use laser printing, a form of electrophotography, to print metal chalcogenide complexes on paper, is described. After fusing the toner to paper, a heating step is used to cause the printed metal xanthate complexes to thermolyze within the toner and form three target metal chalcogenides: CuS, SnS, and ZnS. To achieve this, we synthesize a poly(styrene-co-n-butyl acrylate) thermopolymer that emulates the thermal properties of a commercial toner and is also solution processable with the metal xanthate complexes used: [Zn(S2COEt)2], [Cu(S2COEt)·(PPh3)2], and [Sn(S2COEt)2]. We demonstrate through energy dispersive X-ray mapping that the toner is deposited following printing and that thermolysis of the metal xanthate complexes occurs in the fused toner, demonstrating the first example of laser printing of inorganic complexes and, in turn, semiconductors.

Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders.

Importance: The risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders. Objective: To examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices. Design, Setting, and Participants: The design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques. Main Outcomes and Measures: Outcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments. Results: Layer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated by CALB1 (calbindin), and high levels of CACNA1C (Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by ß1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or ß1-adrenoceptor antagonist protected working memory from stress. Conclusions and Relevance: The layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 (CACNA1C), GluN2B-NMDA receptors (GRIN2B), and SK3 potassium channels (KCNN3), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants in CACNA1C were associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.

Studies of the Crystallization and Dissolution of Individual Suspended Sodium Chloride Aerosol Particles.

Aerosols transform between physical phases, as they respond to variations in environmental conditions. There are many industries that depend on these dynamic processes of crystallization and dissolution. Here, a single particle technique (an electrodynamic balance) is used to explore the crystallization and dissolution dynamics of a model system, sodium chloride. The physical and environmental factors that influence the dynamics of crystal formation from a saline droplet (whose initial radius is ∼25 µm) and the kinetics of water adsorption onto dried particles are examined. The drying relative humidity (RH) is shown to impact the physical properties of the dried particle. When a saline droplet is injected into an airflow at an RH close to the efflorescence RH (ERH, 45%), an individual single crystal forms. By contrast, when a compositionally equivalent saline droplet is injected into dry air (RH ∼ 0%), a salt crystal made of multiple crystalline particles is formed. Subsequent to crystallization, the crystal shape, morphology, and surface area were all found to affect the dissolution dynamics of the dried particle. Additionally, we report that the difference between the deliquesce RH and environmental RH significantly impacts the dissolution time scale.

Investigation of dosimetric characteristics of radiochromic film in response to alpha particles emitted from Americium-241.

BACKGROUND: In radiotherapy, it is essential to deliver prescribed doses to tumors while minimizing damage to surrounding healthy tissue. Accurate measurements of absorbed dose are required for this purpose. Gafchromic® external beam therapy (EBT) radiochromic films have been widely used in radiotherapy. While the dosimetric characteristics of the EBT3 model film have been extensively studied for photon and charged particle beams (protons, electrons, and carbon ions), little research has been done on α $\alpha$ -particle dosimetry. α $\alpha$ -emitting radionuclides have gained popularity in cancer treatment due to their high linear energy transfer, short range in tissue, and ability to spare surrounding organs at risk, thereby delivering a more localized dose distribution to the tumor. Therefore, a dose-calibration film protocol for α $\alpha$ -particles is required. PURPOSE: This study aimed to develop a dose-calibration protocol for the α $\alpha$ -particle emitting radionuclide 241Am, using Monte Carlo (MC) simulations and measurements with unlaminated EBT3 films. METHODS: In this study, a MC-based user code was developed using the Geant4 simulation toolkit to model and simulate an 241Am source and an unlaminated EBT3 film. Two simulations were performed: one with voxelized geometries of the EBT3 active volume composition and the other using water. The dose rate was calculated within a region of interest in the voxelized geometries. Unlaminated EBT3 film pieces were irradiated with the 241Am source at various exposure times inside a black box. Film irradiations were compared to a 6-MV photon beam from a Varian TrueBeam machine. The simulated dose rate was used to convert the exposure times into absorbed doses to water, describing a radiochromic-film-based reference dosimetry protocol for α $\alpha$ -particles. The irradiated films were scanned and through an in-house Python script, the normalized pixel values from the green-color channel of scanned film images were analyzed. RESULTS: The 241Am energy spectra obtained from the simulations were in good agreement with IAEA and NIST databases, having differences < $<$ 0.516% for the emitted γ $\gamma$ -rays and produced characteristic x-rays and < $<$ 0.006% for the α $\alpha$ -particles. Due to the short range of α $\alpha$ -particles, there was no energy deposition in the voxels outside the active 241Am source region projected onto the film surface. Thus, the total dose rate within the voxels covering the source was 0.847 ± $\pm$ 0.003 Gy/min within the sensitive layer of the film (LiPCDA) and 0.847 ± $\pm$ 0.004 Gy/min in water, indicating that the active volume can be considered water equivalent for the 241Am beam quality. A novel approach was employed in α $\alpha$ -film dosimetry using an exponential fit for the green channel, which showed promising results by reducing the uncertainty in dose estimation within 5%. Although the statistical analysis did not reveal significant differences between the 6-MV photon beam and the α $\alpha$ calibration curves, the dose-response curves exhibited the expected behavior. CONCLUSIONS: The developed MC user code simulated the experimental setup for α $\alpha$ -dosimetry using radiochromic film with acceptable uncertainty. Unlaminated EBT3 film is suitable for the dosimetry of α $\alpha$ -radiation at low doses and can be used in conjunction with other unlaminated GafChromic® films for quality assurance and research purposes.

Multicentre double-blind randomised placebo-controlled trial evaluating the efficacy of the meningococcal B vaccine, 4CMenB (Bexsero), against Neisseria gonorrhoeae infection in men who have sex with men: the GoGoVax study protocol.

INTRODUCTION: Gonorrhoea, the sexually transmissible infection caused by Neisseria gonorrhoeae, has a substantial impact on sexual and reproductive health globally with an estimated 82 million new infections each year worldwide. N. gonorrhoeae antimicrobial resistance continues to escalate, and disease control is largely reliant on effective therapy as there is no proven effective gonococcal vaccine available. However, there is increasing evidence from observational cohort studies that the serogroup B meningococcal vaccine four-component meningitis B vaccine (4CMenB) (Bexsero), licensed to prevent invasive disease caused by Neisseria meningitidis, may provide cross-protection against the closely related bacterium N. gonorrhoeae. This study will evaluate the efficacy of 4CMenB against N. gonorrhoeae infection in men (cis and trans), transwomen and non-binary people who have sex with men (hereafter referred to as GBM+). METHODS AND ANALYSIS: This is a double-blind, randomised placebo-controlled trial in GBM+, either HIV-negative on pre-exposure prophylaxis against HIV or living with HIV (CD4 count >350 cells/mm3), who have had a diagnosis of gonorrhoea or infectious syphilis in the last 18 months (a key characteristic associated with a high risk of N. gonorrhoeae infection). Participants are randomised 1:1 to receive two doses of 4CMenB or placebo 3 months apart. Participants have 3-monthly visits over 24 months, which include testing for N. gonorrhoeae and other sexually transmissible infections, collection of demographics, sexual behaviour risks and antibiotic use, and collection of research samples for analysis of N. gonorrhoeae-specific systemic and mucosal immune responses. The primary outcome is the incidence of the first episode of N. gonorrhoeae infection, as determined by nucleic acid amplification tests, post month 4. Additional outcomes consider the incidence of symptomatic or asymptomatic N. gonorrhoeae infection at different anatomical sites (ie, urogenital, anorectum or oropharynx), incidence by N. gonorrhoeae genotype and antimicrobial resistance phenotype, and level and functional activity of N. gonorrhoeae-specific antibodies. ETHICS AND DISSEMINATION: Ethical approval was obtained from the St Vincent's Hospital Human Research Ethics Committee, St Vincent's Hospital Sydney, NSW, Australia (ref: 2020/ETH01084). Results will be disseminated in peer-reviewed journals and via presentation at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04415424.

Multi-scale in vivo imaging of tumour development using a germline conditional triple-reporter system.

Imaging reporter genes are indispensable for visualising biological processes in living subjects, particularly in cancer research where they have been used to observe tumour development, cancer cell dissemination, and treatment response. Engineering reporter genes into the germline frequently involves single imaging modality reporters operating over limited spatial scales. To address these limitations, we developed an inducible triple-reporter mouse model (Rosa26LSL - NRL) that integrates reporters for complementary imaging modalities, flfluorescence, bioluminescence and positron emission tomography (PET), along with inducible Cre-lox functionality for precise spatiotemporal control of reporter expression. We demonstrated robust reporter inducibility across various tissues in the Rosa26LSL - NRL mouse, facilitating effective tracking and characterisation of tumours in liver and lung cancer mouse models. We precisely pinpointed tumour location using multimodal whole-body imaging which guided in situ lung microscopy to visualise cell-cell interactions within the tumour microenvironment. The triple-reporter system establishes a robust new platform technology for multi-scale investigation of biological processes within whole animals, enabling tissue-specific and sensitive cell tracking, spanning from the whole-body to cellular scales.

Remote Surveillance Technology of Dialysis Arteriovenous Access: Retrospective Evaluation in a UK Renal Centre.

BACKGROUND: Early identification of dysfunctional arteriovenous haemodialysis (HD) vascular access (VA) is important for timely referral and intervention. METHOD: We retrospectively calculated VA risk score using Vasc-Alert surveillance software technology from HD treatment sessions in 2 satellite HD units over 18 months. We included in the analysis HD patients dialysing with arteriovenous fistula or graft (AVF/G) with available Vasc-Alert data for≥ 2 months. For group one (eventful) that included patients who developed vascular access thrombosis or stenosis over the study period, we collected Vasc-Alert risk score 2 months prior to the event and, for group two (uneventful), over 5 consecutive months. Vasc-Alert technology utilises routinely collected data during HD to calculate VA risk score and triggers an alert if the score is ≥7 in 3 consecutive dialysis sessions. Patients with >2 alerts (vascular access score ≥7) per month were considered to have positive alerts. RESULTS: From 140 HD patients, 81 patients dialysed via AVF/G. 77/81 had available Vasc-Alert data and were included in the final analysis. Out of 17 eventful patients, 11 (64.7%) had positive alerts 2 months prior to the vascular event. Out of the 60 patients without vascular events, 20 patients (33.3%) had positive alert. Vasc-Alert's sensitivity and specificity for vascular events were 64.7% and 66.6%, respectively. Within the 6 patients with thrombosed access, 2 patients (33.3%) detected by Vasc-Alert were not detected with clinical monitoring. CONCLUSION: Vascular access risk score can be a useful non-invasive vascular access surveillance method to assist clinical decision making.

Multi-institutional evaluation of a Pareto navigation guided automated radiotherapy planning solution for prostate cancer.

BACKGROUND: Current automated planning solutions are calibrated using trial and error or machine learning on historical datasets. Neither method allows for the intuitive exploration of differing trade-off options during calibration, which may aid in ensuring automated solutions align with clinical preference. Pareto navigation provides this functionality and offers a potential calibration alternative. The purpose of this study was to validate an automated radiotherapy planning solution with a novel multi-dimensional Pareto navigation calibration interface across two external institutions for prostate cancer. METHODS: The implemented 'Pareto Guided Automated Planning' (PGAP) methodology was developed in RayStation using scripting and consisted of a Pareto navigation calibration interface built upon a 'Protocol Based Automatic Iterative Optimisation' planning framework. 30 previous patients were randomly selected by each institution (IA and IB), 10 for calibration and 20 for validation. Utilising the Pareto navigation interface automated protocols were calibrated to the institutions' clinical preferences. A single automated plan (VMATAuto) was generated for each validation patient with plan quality compared against the previously treated clinical plan (VMATClinical) both quantitatively, using a range of DVH metrics, and qualitatively through blind review at the external institution. RESULTS: PGAP led to marked improvements across the majority of rectal dose metrics, with Dmean reduced by 3.7 Gy and 1.8 Gy for IA and IB respectively (p < 0.001). For bladder, results were mixed with low and intermediate dose metrics reduced for IB but increased for IA. Differences, whilst statistically significant (p < 0.05) were small and not considered clinically relevant. The reduction in rectum dose was not at the expense of PTV coverage (D98% was generally improved with VMATAuto), but was somewhat detrimental to PTV conformality. The prioritisation of rectum over conformality was however aligned with preferences expressed during calibration and was a key driver in both institutions demonstrating a clear preference towards VMATAuto, with 31/40 considered superior to VMATClinical upon blind review. CONCLUSIONS: PGAP enabled intuitive adaptation of automated protocols to an institution's planning aims and yielded plans more congruent with the institution's clinical preference than the locally produced manual clinical plans.